Novel pathophysiological insight and treatment strategies for heart failure--lessons from mice and patients--.
The ultimate goal of heart failure (HF) treatment is to improve the prognosis of patients. Previous basic, clinical, and population studies have advanced the modern treatment of HF, but efficacy is still limited especially in 'real world' patients. There are 2 approaches to solve this crucial issue. First is the further development of novel therapeutic strategies based on new insight into the pathophysiology of myocardial remodeling and failure. Second is the improvement of the quality of care in routine clinical practice. The basic approach is to develop the treatment of myocardial remodeling by regulating mitochondrial oxidative stress. In the failing heart, oxygen radicals are the result of defects of mitochondrial electron transport, causing mitochondrial DNA damage and functional decline, and further production of oxygen radicals. Oxidative stress causes myocyte hypertrophy, apoptosis, and interstitial fibrosis by activating matrix metalloproteinases, all of which result in myocardial remodeling and failure. Therefore, mitochondrial oxidative stress and DNA damage are good therapeutic targets. The clinical approach is to develop effective strategies of HF management for the 'real world' patients. Readmission because of exacerbation is common in HF patients and further impairs their quality of life. Noncompliance with treatment is the most common precipitating factor for readmission. Regular medical follow-up and social support are important components that should be included in the disease management program of HF patients. These basic and clinical approaches are needed to establish new and effective treatment strategies for Japanese patients with HF.


Modified Interim Mandibular Advancement (MIMA) Appliance for Symptomatic Correction of Obstructive Sleep Apnea.
Obstructive Sleep Apnea (OSA) is a chronic, progressive, multifactorial, life-threatening disorder that causes significant impact on patient's life. Patients with OSA [Apnea/Hypopnea Index (AHI)>30] who cannot tolerate Continuous Positive Airway Pressure (CPAP) therapy or are not surgical candidates may benefit from oral appliances. This paper describes interim appliance devised from existing Hawley's retainer in patients with OSA. A 38-year-old man of athletic built with history of orthodontic treatment six months back due to esthetic concerns and wearing upper Hawley's retainer, reported with chief complaint of frequent nocturnal awakening along with excessive daytime somnolence. Based on diagnostic aids, he was diagnosed with Class II Division 1 malocclusion with severe mandibular retrusion. Sleep test revealed AHI score of 34, suggestive of severe OSA. With ENT and Oral surgeon concurrence, mandibular advancement of 7mm with Bilateral Sagital Split Osteotomy (BSSO) with distraction was contemplated as a viable functional and curative stable treatment plan. Because of non-adherence and non-compliance with CPAP therapy and on request of patient, an interim anterior positioning appliance was devised to facilitate comfortable sound sleep till the time surgery is impending. After three months of wearing this customized appliance, improved quality of sleep was discernible; both subjectively as reported by patient and objectively using sleep test (AHI=9.8).


Ultrasound examination of the normal pancreas.
The pancreas is a challenge for the beginner in ultrasonography, but patience, perseverance and experience will lead to a complete and correct evaluation of the organ in almost all cases. A correct examination of the pancreas requires the patient's fasting 7 to 8 hours before the examination. Transverse and longitudinal upper epigastric sections are used to visualize the pancreas, as well as oblique intercostal and subcostal sections (especially for the head and tail). The best ultrasound windows are obtained by using high epigastric sections (that avoid the colon), also by using transgastric sections and sections that use the left liver lobe as an acoustic window. In order to better visualize the pancreas, it is useful to invite the patient to drink 500-700 ml of still water 10-15 minutes before the examination. To highlight the pancreas, we will start by viewing the landmarks: posterior--the porto-splenic axis and anterior--the gastric antrum and/or the left liver lobe. The echogeneity of the normal pancreas can vary, from hypoechoic to hyperechoic, all normal, provided that the pancreatic parenchyma structure is fine and homogeneous. The Wirsung duct can be visualized in some of the cases, especially in thin patients, its normal maximum diameter should be < 2 mm. For a correct evaluation of the pancreas all its segments must be visualized: head, uncinate process, body, and tail - the latter being the most difficult to visualize.


Controlled Mass Rearing of Cochineal Insect (Hemiptera: Dactylopiidae) Using Two Laboratory-Scale Production Systems in Peru.
The carmine cochineal (Dactylopius coccus Costa) has high economic value as it is a natural source of carminic acid, an organic chromophore used in a wide range of sectors including pharmaceutics, food, and cosmetics. High demand is fuelling the search for innovative production techniques in order to move away from dependence on the prickly pear, which carries a number of limitations. The aim of this study was to establish cochineal colonies and breed and mass-produce the insects using two laboratory-scale production systems. The first system (STC-01) comprised a prismatic acrylic box with three compartments; synthetic matrices were placed vertically inside the box to provide support and a source of nutrients for the cochineal, and the system was lit artificially during fixed daylight periods. The second system (STC-02) comprised an automated micro-tunnel allowing the insects to move towards the sunlight, containing synthetic matrices arranged horizontally. There was a significant difference in yield between the two systems in a cochineal total life cycle of 120 d (80-90 d harvest period in both cases), with STC-01 being superior and producing a maximum yield of 4.86 ± 0.68 g fresh weight per day per square metre compared with 3.20 ± 0.14 g fresh weight per day per square metre production yield in STC-02. We conclude that cochineal production under controlled artificial conditions is feasible and sustainable, removing the need for natural and biological support and overcoming the environmental limitations posed by traditional production methods.


Need for including Hand Eye Coordination and Hand Function Training in the Management of Adhesive Capsulitis - A non-randomized control trial.
The objective of the study was to identify the effect of Maitland mobilization with hand-eye coordination and hand function exercises in the prognosis of adhesive capsulitis. This non-randomized control trial was done with 40 patients with adhesive capsulitis referred to the OPD at UCA College of Physiotherapy, Chennai. The study was performed for 8 months duration from August 2018 to March 2019. After providing a sufficient explanation of the procedure, the patients were divided into Group-A and Group-B. Group-A were allocated to Maitland group (n=20) (MG) and Group-B, were assigned to the Maitland, Hand-eye coordination and Hand Function exercises group (n=20) (MHG), respectively. We measured Quality of life using SF36 to know whether these patients had poor QOL compared to normative. Each patient underwent testing before the experiment to evaluate the range of motion of the shoulder (Abduction and External rotation) measured using a 180º goniometer, Functional Disability assessed using SPADI index. Statistical analysis was applied using SPSS version 20.0. Before the study, data normality was tested. A parametric test was used to compare pre-and post-intervention data in each Group-And also compare the MG vs. MHG. An α < 0.05 is the level of significance in all analyses. A total of 40 subjects accounted for the study results. Their quality of life was significantly lower from the normative values. Both groups were homogenous at baseline with no significant difference between the ROM and SPADI scores. Both groups showed a significant improvement in ER, abduction ROM and SPADI scores, however the between group posttest analysis revealed that the Group-B subjects progressed significantly better. The study concluded that the Maitland mobilization and hand-eye coordination and hand function exercises are an effective tool in improving shoulder abduction, external rotation and shoulder functions.


Is Visible Aminolevulinic Acid-Induced Fluorescence an Independent Biomarker for Prognosis in Histologically Confirmed (World Health Organization 2016) Low-Grade Gliomas?
Approximately 20% of low-grade gliomas (LGG) display visible protoporphyrin fluorescence during surgery after 5-aminolevulinic acid (5-ALA) administration. To determine if fluorescence represents a prognostic marker in LGG. Seventy-four consecutive patients with LGG (World Health Organization 2016) were operated on with 5-ALA. Fluorescent tissue was specifically biopsied. Tumor size, age, Karnofsky index, contrast-enhancement, fluorescence, and molecular factors (IDH1/IDH2-mutations, Ki67/MIB1 Index, 1p19q codeletions, ATRX, EGFR, p53 expression, and O6-methylguanine DNA methyltransferase promotor methylation), were related to progression-free survival (PFS), malignant transformation-free survival (MTFS) and overall survival (OS). Sixteen of seventy-four LGGs (21.6%) fluoresced. Fluorescence was partially related to weak enhancement on magnetic resonance imaging and increased (positron emission tomography)PET-FET uptake, but not to Karnofsky Performance Score, tumor size, or age. Regarding molecular markers, only EGFR expression differed marginally (fluorescing vs nonfluorescing: 19% vs 5%; P = .057). Median follow-up was 46.4 mo (95% confidence interval [CI]: 41.8-51.1). PFS, MTFS, and OS were shorter in fluorescing tumors (PFS: median 9.8 mo, 95% CI: 1.00-27.7 vs 45.8, 31.9-59.7, MTFS: 43.0 [27.5-58.5] vs 64.6 [57.7-71.5], median not reached, P = .015; OS: 51.6, [34.8-68.3] vs [68.2, 62.7-73.8], P = .002). IDH mutations significantly predicted PFS, MTFS, and OS. In multivariate analysis IDH status and fluorescence both independently predicted MTFS and OS. PFS was not independently predicted by fluorescence. This is the first report investigating the role of ALA-induced fluorescence in histologically confirmed LGG. Fluorescence appeared to be a marker for inherent malignant transformation and OS, independently of known prognostic markers. Fluorescence in LGG might be taken into account when deciding on adjuvant therapies.


Hospitalization for Failure to Thrive: A Prospective Descriptive Report.
Failure to thrive (FTT) is a common symptom leading to hospitalization of children. Most literature describing this population is from 30 years ago. Since that time the hospitalized population has become more medically complex. We aimed to describe children hospitalized for FTT in a tertiary care pediatric hospital. We prospectively collected demographic, anthropometric, evaluation, and outcome data for 92 consecutive children admitted with FTT. The majority of children grew with behavioral interventions alone (primary nonorganic FTT) and had negative evaluation (n = 63). Children with primary organic FTT had longer hospital stays (7 vs 4 days; P < .001) and lower daily weight gain (35 vs 58 g/d; P < .001). Laboratory, radiological, and endoscopic evaluation rarely led to a diagnostic etiology of FTT in hospitalized children. We conclude that children hospitalized with FTT should be observed for weight gain prior to pursuing diagnostic investigation.


Benjamin Franklin's place in the history of medicine.
Benjamin Franklin's seemingly endless curiosity and his prolific contributions in diplomacy, politics, literature, and science may well justify calling him the most eminent man in eighteenth-century American life. One portion of these contributions still striking for the insights and productivity it shows was in medicine. He saw the value in inoculation against smallpox. He was aware of the placebo effect. He, in effect, launched the first American medical school. He devised a flexible urethral catheter. He identified lead poisoning as a cause of abdominal pain and peripheral neuropathy. He accurately described psoriasis well before RobertWillan. These contributions in medicine of his time were not then notably influential, but they certainly illustrate the versatility of his intellect.


Standardized tests of heart rate variability for autonomic function tests in healthy Koreans.
Heart rate variability (HRV) is a noninvasive measure of autonomic input to heart rate that has been successfully used to estimate modulation of autonomic tone. The authors investigated to determine the normal ranges as a standardized tests of heart rate variability (HRV) for autonomic function tests in a large sample of healthy Koreans. The study also evaluated the effects of age, sex, and heart rate (HR) on the results of HRV and the values of HRV in hypertension, diabetes, and obesity group. Six hundred and thirty-seven healthy subjects who visited the health improvement center for medical examination were evaluated. A standardized 5-min resting study, including spectral analysis of HR, was used to all participants after an overnight fast. HRV (SA-2000E, Medicore, Korea) was spectrally determined by three components: total-frequency (TF) component (0.01 to 0.5 Hz), low-frequency (LF) component (0.04 to 0.15 Hz), and high-frequency (HF) component (0.15 to 0.5 Hz). Also two component ratio (LF/HF) was calculated. Routine laboratory and physical examinations were used to eliminate cardiovascular diseases and neurological disorders. The determinants of short-period HRV in a random sample of 366 men and 271 women from healthy subjects were assessed. The mean age of these subjects was 45.1 +/- 10.7 years. The mean value of total power was 1106.9 +/- 1109.1 ms(2); SDNN was 35.9 +/- 15.5 ms; rMSSD was 27.3 +/- 15.6 ms for time domain analysis. The mean value of LF was 287.5 +/- 384.1 ms(2); HF was 227.0 +/- 284.4 ms(2); LF/HF was 2.2 +/- 3.4 for frequency domain analysis. Additionally, men showed that their TP, LF, and LF/HF values were significantly higher than women whereas SDNN, rMSSD, HF showed no significant differences between sexes. With increasing age, there was no significant decrease in HR. TP, SDNN, LF, and HF were significantly decreased when getting older. On the contrary, LF/HF had no significant difference related to age. The study confirmed that SDNN and rMSSD were significantly lower in hypertension and diabetes group. In conclusion, middle-aged men had more pronounced sympathetic influence than women in cardiac regulation, and HRV declined linearly with age. In addition, HRV reflecting the function of autonomic nervous system was decreased in hypertension and diabetes group.


Recurrent lentigo maligna invading a skin graft successfully treated with Mohs' micrographic surgery.
Lentigo maligna (LM) is a pigmented lesion occurring on sun-exposed skin that may become lentigo maligna melanoma (LMM). The tumor can behave in an aggressive fashion, causing significant cosmetic disfigurement, often extending significantly further than the clinical margin. Complete surgical excision is the treatment of choice. We describe a 74-year-old woman with a large LM of the left cheek, upper and lower eyelids, and preauricular skin that had recurred twice. The tumor was removed using Mohs' micrographic surgery (MMS) with rush permanent sections and was found to infiltrate extensively the split-thickness skin graft that had been placed five years earlier. LM can invade and replace a skin graft. Although destructive modalities and conventional surgery are recommended by some authors, MMS offers the greatest likelihood of cure, the ability to examine nearly 100 percent of the surgical margins, and maximal tissue sparing. Complete excision of LM at its earliest recognition may prevent invasive LMM and will limit cosmetic disfigurement.


[The specificity of lipid metabolism in hereditary arterial hypertension induced by stress].
Studies of lipid metabolites in the plasma and lymph of rats with hereditary arterial hypertension induced by stress (HAHIS) showed decreased plasma and lymph pool of total cholesterol (TC) in comparison with normotensive Wistar rats. In HAHIS animals, TC concentration in the lymph was lower than in the plasma. The concentrations of triglycerides and free fatty acids in the plasma and lymph of hypertensive animals were virtually the same and higher than in normotensive ones. Plasma concentration of malonic dialdehyde (MDA) in HAHIS rats was the same as in Wistar rats, while the lymph concentration of MDA was higher than in Wistar rats. The detected lipid metabolism characteristics reflect its genotypical and phenotypical rearrangement and are a component of the "metabolic syndrome", detected in patients with essential hypertension and animals with spontaneous arterial hypertension.


Detection and characterization of a high molecular weight human lung carcinoma-associated glycoprotein.
We have defined a human lung carcinoma antigen using murine monoclonal antibodies (DF-L1 and DF-L2) prepared against a primary adenocarcinoma of the lung. This antigen is expressed on the surface of human lung carcinoma cell lines and has an apparent Mr of 350,000-420,000. Immunoperoxidase staining has demonstrated expression of the antigen in the cytoplasm and membranes of adenocarcinomas and squamous cell carcinomas but not small cell tumors of the lung. Immunoprecipitation of the antigen following radiolabeling has demonstrated the presence of both protein and carbohydrate. Antigen purified by immunoaffinity was used to study the epitopes defined by monoclonal antibodies DF-L1 and DF-L2. The results indicate that the DF-L1 epitope primarily involves a peptide structure, while the DF-L2 epitope is comprised in part by peptide and O-linked carbohydrate. In contrast, there was no detectable evidence for the presence of N-linked glycosylation. The results also demonstrate that this antigen circulates at elevated levels in patients with carcinoma of the lung. These findings are similar to previous reports of high molecular weight glycoproteins in breast and ovarian carcinomas. Indeed, the present results in lung cancer identify another member of this heterogeneous family of human carcinoma-associated glycoproteins.


Compound K, a metabolite of ginseng saponin, induces mitochondria-dependent and caspase-dependent apoptosis via the generation of reactive oxygen species in human colon cancer cells.
The objective of this study was to elucidate the cytotoxic mechanism of Compound K, with respect to the involvement of reactive oxygen species (ROS) and the mitochondrial involved apoptosis, in HT-29 human colon cancer cells. Compound K exhibited a concentration of 50% growth inhibition (IC(50)) at 20 μg/mL and cytotoxicity in a time dependent manner. Compound K produced intracellular ROS in a time dependent fashion; however, N-acetylcysteine (NAC) pretreatment resulted in the inhibition of this effect and the recovery of cell viability. Compound K induced a mitochondria-dependent apoptotic pathway via the modulation of Bax and Bcl-2 expressions, resulting in the disruption of the mitochondrial membrane potential (Δψ(m)). Loss of the Δψ(m) was followed by cytochrome c release from the mitochondria, resulting in the activation of caspase-9, -3, and concomitant poly ADP-ribosyl polymerase (PARP) cleavage, which are the indicators of caspase-dependent apoptosis. The apoptotic effect of Compound K, exerted via the activation of c-Jun NH(2)-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK), was abrogated by specific MAPK inhibitors. This study demonstrated that Compound K-mediated generation of ROS led to apoptosis through the modulation of a mitochondria-dependent apoptotic pathway and MAPK pathway.


A 5-Week Seminar on the Biopsychosocial-Spiritual Model of Self-Care Improves Anxiety, Self-Compassion, Mindfulness, Depression, and Stress in Graduate Healthcare Students.
Graduate healthcare students can experience stress that affects their ability to perform academically and clinically, decreases empathy, and affects their well-being and clinical competence. The purpose of the current study was to determine the effects of a seminar on a yoga-inspired biopsychosocial-spiritual model of self-care on perceived levels of anxiety, self-compassion, mindfulness, depression, and stress in graduate healthcare students. We used a within-group repeated-measure design with baseline followed by intervention. The intervention was a 5-week seminar with 60-minute sessions that incorporated breathing, mindful movement, meditation, and education for self-care in five areas of a biopsychosocial-spiritual model (spiritual, physical, intellectual, energetic, and psychoemotional-social). The following outcomes measures assessed perceived changes in anxiety, self-compassion, mindfulness, depression, and stress: Beck Anxiety Inventory (BAI), Self-Compassion Scale-Short Form (SCS-SF), Freiburg Mindfulness Inventory (FMI), Kentucky Inventory of Mindfulness Skills (KIMS), Mindfulness Attention Awareness Scale (MAAS), Beck Depression Inventory (BDI), and Perceived Stress Scale (PSS). The Freidman test with Dunn's test post hoc pairwise comparisons was used for the BAI, SCS-SF, FMI, KIMS, and MAAS. A Wilcoxon signed-rank test was used for BDI and PSS. Twenty doctor of physical therapy students and one doctor of dental medicine student participated in the study. Significant improvements (all p < 0.05) were found for self-compassion, mindfulness, anxiety, depression, and stress. A 5-week seminar using a biopsychosocial-spiritual approach for self-care improved self-compassion and mindfulness and diminished anxiety, depression, and stress. Implementing programs that facilitate self-awareness and self-care may provide important benefits to future healthcare providers.


Age at menarche, schooling, and sexual debut in northern Malawi.
Age at sexual debut is a key behavioural indicator used in HIV behavioural surveillance. Early age at menarche may precipitate early sex through perceived readiness for sex, or through school drop-out, but this is rarely studied. We investigated trends and circumstances of sexual debut in relation to schooling and age at menarche. A cross-sectional sexual behaviour survey was conducted on all individuals age 15-59 within a demographic surveillance site in Karonga District, Malawi. Time trends were assessed using birth cohorts. Survival analysis was used to estimate the median age at menarche, sexual debut and first marriage. The 25(th) centile was used to define "early" sex, and analyses of risk factors for early sex were restricted to those who had reached that age, and were done using logistic regression. Of the 8232 women and 7338 men resident in the area, 88% and 78%, respectively, were seen, and, 94% and 92% of these were interviewed. The median reported age at first sex was 17.5 for women and 18.8 for men. For women, ages at menarche, sexual debut and first marriage did not differ by birth cohort. For men, age at sexual debut and first marriage decreased slightly in later birth cohorts. For both men and women increased schooling was associated with later sexual debut and a longer delay between sexual debut and first marriage, but the associations were stronger for women. Earlier age at menarche was strongly associated with earlier sexual debut and marriage and lower schooling levels. In women early sexual debut (<16 years) was less likely in those with menarche at age 14-15 (odds ratio (OR) 0.31, 95%CI 0.26-0.36), and ≥16 (OR 0.04, 95%CI 0.02-0.05) compared to those with menarche at <14. The proportion of women who completed primary school was 46% in those with menarche at <14, 60% in those with menarche at 14-15 and 70% in those with menarche at ≥16. The association between age at menarche and schooling was partly explained by age at sexual debut. The association between age at menarche and early sex was not altered by adjusting for schooling. Women with early menarche start sex and marry early, leading to school drop-out. It is important to find ways to support those who reach menarche early to access the same opportunities as other young women.


Model-Guided Deep Hyperspectral Image Super-Resolution.
The trade-off between spatial and spectral resolution is one of the fundamental issues in hyperspectral images (HSI). Given the challenges of directly acquiring high-resolution hyperspectral images (HR-HSI), a compromised solution is to fuse a pair of images: one has high-resolution (HR) in the spatial domain but low-resolution (LR) in spectral-domain and the other vice versa. Model-based image fusion methods including pan-sharpening aim at reconstructing HR-HSI by solving manually designed objective functions. However, such hand-crafted prior often leads to inevitable performance degradation due to a lack of end-to-end optimization. Although several deep learning-based methods have been proposed for hyperspectral pan-sharpening, HR-HSI related domain knowledge has not been fully exploited, leaving room for further improvement. In this paper, we propose an iterative Hyperspectral Image Super-Resolution (HSISR) algorithm based on a deep HSI denoiser to leverage both domain knowledge likelihood and deep image prior. By taking the observation matrix of HSI into account during the end-to-end optimization, we show how to unfold an iterative HSISR algorithm into a novel model-guided deep convolutional network (MoG-DCN). The representation of the observation matrix by subnetworks also allows the unfolded deep HSISR network to work with different HSI situations, which enhances the flexibility of MoG-DCN. Extensive experimental results are reported to demonstrate that the proposed MoG-DCN outperforms several leading HSISR methods in terms of both implementation cost and visual quality. The code is available at https://see.xidian.edu.cn/faculty/wsdong/Projects/MoG-DCN.htm.


The pandemic predominantly hits poor neighbourhoods? SARS-CoV-2 infections and COVID-19 fatalities in German districts.
Reports from the UK and the USA suggest that coronavirus disease 2019 (COVID-19) predominantly affects poorer neighbourhoods. This article paints a more complex picture by distinguishing between a first and second phase of the pandemic. The initial spread of infections and its correlation with socio-economic factors depends on how the virus first entered a country. The second phase of the pandemic begins when individuals start taking precautionary measures and governments implement lockdowns. In this phase, the spread of the virus depends on the ability of individuals to socially distance themselves, which is to some extent socially stratified. We analyze the geographical distribution of known cumulative cases and fatalities per capita in an ecological analysis across local districts in Germany distinguishing between the first and the second phase of the pandemic. In Germany, the virus first entered via individuals returning from skiing in the Alps and other international travel. In this first phase, we find a positive association between the wealth of a district and infection rates and a negative association with indicators of social deprivation. During the second phase and controlling for path dependency, districts with a higher share of university-educated employees record fewer new infections and deaths and richer districts record fewer deaths, districts with a higher unemployment rate record more deaths. The social stratification of COVID-19 changes substantively across the two phases of the pandemic in Germany. Only in the second phase and controlling for temporal dependence does COVID-19 predominantly hit poorer districts.


[Treatment of erectile dysfunction with vacuum devices].
To analyze the results achieved with vacuum devices in the treatment of erectile dysfunction. A telephone survey was conducted on 150 patients undergoing treatment with a vacuum device. Of these, 89 responded; 79 of which were considered valid for the study. The duration and frequency of use, side effects and degree of patient and partner satisfaction were analyzed. Mean follow-up was 59.5 months. There were 14 dropouts early in the course of treatment. The remaining 65 patients used the device for a mean duration of 34.6 months, 3.7 times monthly. 63.3% of the patients achieved erection in more than half of the attempts. The most frequent side effects were pain (27 patients) and ecchymosis (7 patients). Forty-eight patients discontinued treatment at 10.8 months' mean follow-up. The most common causes for discontinuing treatment were lack of efficacy, refusal of the partner and pain. Treatment of erectile dysfunction with the vacuum constriction device should be utilized as an alternative to intracavernosal drug-induced erection therapy when oral therapy fails or is contraindicated. A male with a stable partner and impotence arising from venous leakage or mild cavernous artery insufficiency is the ideal candidate.


Priority setting and equity in COVID-19 pandemic plans: a comparative analysis of 18 African countries.
Priority setting represents an even bigger challenge during public health emergencies than routine times. This is because such emergencies compete with routine programmes for the available health resources, strain health systems and shift health-care attention and resources towards containing the spread of the epidemic and treating those that fall seriously ill. This paper is part of a larger global study, the aim of which is to evaluate the degree to which national COVID-19 preparedness and response plans incorporated priority setting concepts. It provides important insights into what and how priority decisions were made in the context of a pandemic. Specifically, with a focus on a sample of 18 African countries' pandemic plans, the paper aims to: (1) explore the degree to which the documented priority setting processes adhere to established quality indicators of effective priority setting and (2) examine if there is a relationship between the number of quality indicators present in the pandemic plans and the country's economic context, health system and prior experiences with disease outbreaks. All the reviewed plans contained some aspects of expected priority setting processes but none of the national plans addressed all quality parameters. Most of the parameters were mentioned by less than 10 of the 18 country plans reviewed, and several plans identified one or two aspects of fair priority setting processes. Very few plans identified equity as a criterion for priority setting. Since the parameters are relevant to the quality of priority setting that is implemented during public health emergencies and most of the countries have pre-existing pandemic plans; it would be advisable that, for the future (if not already happening), countries consider priority setting as a critical part of their routine health emergency and disease outbreak plans. Such an approach would ensure that priority setting is integral to pandemic planning, response and recovery.


Validated Analytical Methods for the Determination of Drugs Used in the Treatment of Hyperemesis Gravidarum in Multiple Formulations.
Quantitative multicomponent analysis is considered an analytical goal to save time and cost in analysis. Hence, this work aimed to provide sensitive and selective UV-spectrophotometric, chemometric manipulation, and ultra-performance LC (UPLC) methods for the determination of well-known coformulated antiemetics used in pregnancy, namely pyridoxine HCl (PYR), meclozine HCl, and cyclizine. The developed UV-spectrophotometric methods are dual wavelength in ratio spectra and first derivative of the ratio spectra with which PYR was determined selectively at 290.8 nm, whereas the other drugs in a ternary mixture were determined from their ratio spectra using a spectrum of PYR as a divisor in 0.1 M HCl. An ecofriendly partial least-squares regression chemometric method was applied to raw UV absorbance data for the determination of the ternary mixture in a 218-355 nm range using a three-factor, three-level design with water as the green solvent. A gradient UPLC method was developed and successfully resolved the ternary mixture within 5 min. Different ratios of water (adjusted to pH 3 with phosphoric acid) and methanol were delivered at 0.5 mL/min as the mobile phase into a Hypersil Gold C18 column (50 × 2.1 mm, 1.9 µm). The developed methods were successfully applied to different pharmaceutical formulations containing the aforementioned drugs and validated according to the International Conference on Harmonization guidelines. The results obtained were reproducible and reliable and can be applied for routine analysis and QC in laboratories.


Manipulation of Recrystallization and Network Formation of Oil-Dispersed Micronized Fat Crystals.
A detailed investigation was carried out on the modulation of the coupling between network formation and the recrystallization of oil-dispersed micronized fat crystal (MFC) nanoplatelets by varying oil composition, shear, and temperature. Sunflower (SF) and bean (BO) oils were used as dispersing media for MFC nanoplatelets. During MFC dispersion production at high shear, a significant increase in the average crystal thickness (ACT) could be observed, pointing to recrystallization of the MFC nanoplatelets. More rapid recrystallization of MFC occurred in the SF dispersion than in the BO dispersion, which is attributed to higher solubility of MFC in the SF oil. When the dispersions were maintained under low shear in narrow gap Couette geometry, we witnessed two stages of recrystallization (measured via rheo-SAXD) and the development of a local yield stress (measured via rheo-MRI). In the first stage, shear-enabled mass transfer induces rapid recrystallization of randomly distributed MFC nanoplatelets, which is reflected in a rapid increase in ACT (rheo-SAXD). The formation of a space-filling weak-link MFC network explains the increase in yield stress (assessed in real time by rheo-MRI). In this second stage, recrystallization slows down and yield stress decreases as a result of the formation of MFC aggregates in the weak link network, as observed by confocal Raman imaging. The high fractal dimension of the weak-link network indicates that aggregation takes place via a particle-cluster mechanism. The effects of oil type and shear on the recrystallization rate and network strength could be reproduced in a stirred bowl with a heterogeneous shear stress field, which opens perspectives for the rational manipulation of MFC thickness and network strength under industrial processing conditions.


High-Intensity Conditioning Activity Causes Localized Postactivation Performance Enhancement and Nonlocalized Performance Reduction.
Kolinger D, Stastny P, Pisz A, Krzysztofik M, Wilk M, Tsoukos A, and Bogdanis GC. High-intensity conditioning activity causes localized postactivation performance enhancement and nonlocalized performance reduction. J Strength Cond Res 38(1): e1-e7, 2024-This study aimed to examine whether a conditioning activity (CA) performed by the legs (barbell back squat) may cause postactivation performance enhancement (PAPE) on muscle groups other than leg extensors in isokinetic (eccentric [ECC] and concentric [CON]) and dynamic movement. Twelve male basketball players (age: 21.3 ± 3.2, body mass: 89.6 ± 14.1 kg, height: 187.4 ± 4.6 cm, and 1 repetition maximum (1RM) barbell back squat: 113 ± 21 kg) with previous resistance-training experience of at least 2 years, performed 3 sets of 3-4 repetitions of back-squats with submaximal load (60, 90, and 90% 1RM) as CA. Before and after the CA, they performed pretest and post-test in the form of countermovement jumps (CMJs) (localized) or explosive push-ups (EPUs) (nonlocalized) along with isokinetic flexion and extension at the knee (localized) or at the elbow (nonlocalized). The localized and nonlocalized protocols were divided into 2 days in a randomized order. The back squat as CA significantly increased peak torque (PT) (p < 0.05) in all CON and ECC muscle actions and average power per repetition (APPR) (p < 0.05) (all muscle actions except ECC flexion) of the localized isokinetic tests with large (>0.8) and medium (0.4-0.79) effect sizes and significantly decreased (p < 0.01) the PT and APPR (p < 0.01) of the nonlocalized isokinetic test in the ECC flexion. The CMJ and EPU tests showed no significant differences (p > 0.05) between premeasures and postmeasures of take-off height. The effect of PAPE seems to be specific to the muscles most involved in the CA, and the CA inhibits PT of subsequent muscle ECC contractions in muscles not involved in the CA.


[Class II malocclusion. Time and cost of a combined orthodontic and surgical treatment].
During orthodontic treatment of 29 patients with a Class II malocclusion, the remaining overjet was corrected surgically by intraoral mandibular distraction osteogenesis. The patients were divided in two groups. Group A was treated orthodontically in a two-phase approach, using functional and fixed appliances. Group B was treated in a one-phase approach with only fixed appliances. Before treatment the differences in age, gender and severity of the malocclusion between the groups, were not statistically significant. After distraction-osteogenesis, all orthodontic treatments could be finished successfully. The mean treatment time was for group A 44.2 and for group B 28.6 months. The difference was statistically significant (p < 0.001). The mean orthodontic treatment time after distraction osteogenesis was 9.1 months. The mean cost for the orthodontic treatment was not statistically significant different between the groups.


Antibiotics' susceptibility patterns of bacterial isolates causing lower respiratory tract infections in ICU patients at referral hospitals in Namibia.
Lower respiratory tract infections (LRTIs) are a particular public health concern especially among sub-Saharan African countries. This is especially the case in Namibia, where LRTIs are currently the third leading cause of death, 300 deaths in children under 5 years of age. To reduce the burden of LRTIs on health systems and ensure appropriate patient management, it is critical to know the most prevalent pathogens leading to LRTIs and their susceptibility patterns in the local setting. Consequently, the objective of this study was to formulate cumulative antibiograms for Intensive Care Units (ICUs) of referral hospitals in Namibia to guide future antibiotic use. A retrospective analytical cross-sectional study was conducted over 2 years. The cumulative antibiograms were constructed in accordance with current guidelines. A total of 976 first isolate cultures were obtained from ICUs of the different referral hospitals. K. pneumoniae (8.8%, 8.1%) was a predominant pathogen in Windhoek Central hospital ICU in 2017 and 2018. In Oshakati intermediate hospital ICU, Enterobacter sp. (22.2%) and P. aeruginosa (37.5%) were the common pathogens in 2017 and 2018, respectively. A. baumannii isolates were >90% susceptibility to colistin, carbapenems, and tigecycline in 2017. In 2017, K. pneumoniae isolates were more susceptible to carbapenems (94% and 93.8% among isolates), amikacin (89.3%), and tigecycline (88.7%). In 2018, K. pneumoniae isolates were 100% susceptible amikacin, colistin, and carbapenems. S. maltophilia isolates were more than 80% susceptible to all the tested antibiotics. S. aureus isolates were 100% susceptible to linezolid, rifampicin, teicoplanin, and vancomycin in 2017 and in 2018. Its susceptibility to these antibiotics did not change. The susceptibility patterns of the common isolated gram-negative pathogens were highly variable. Meropenem in combination with gentamicin is now the recommended antibiotic combination for empiric therapy for patients with LRTIs in Windhoek Central Hospital ICU.


In Vivo Characterization of the Activation and Interaction of the VanR-VanS Two-Component Regulatory System Controlling Glycopeptide Antibiotic Resistance in Two Related Streptomyces Species.
The VanR-VanS two-component system is responsible for inducing resistance to glycopeptide antibiotics in various bacteria. We have performed a comparative study of the VanR-VanS systems from two streptomyces strains, Streptomyces coelicolor and Streptomyces toyocaensis, to characterize how the two proteins cooperate to signal the presence of antibiotics and to define the functional nature of each protein in each strain background. The results indicate that the glycopeptide antibiotic inducer specificity is determined solely by the differences between the amino acid sequences of the VanR-VanS two-component systems present in each strain rather than by any inherent differences in general cell properties, including cell wall structure and biosynthesis. VanR of S. coelicolor (VanRsc) functioned with either sensor kinase partner, while VanR of S. toyocaensis (VanRst) functioned only with its cognate partner, S. toyocaensis VanS (VanSst). In contrast to VanRsc, which is known to be capable of phosphorylation by acetylphosphate, VanRst could not be activated in vivo independently of a VanS sensor kinase. A series of amino acid sequence modifications changing residues in the N-terminal receiver (REC) domain of VanRst to the corresponding residues present in VanRsc failed to create a protein capable of being activated by VanS of S. coelicolor (VanSsc), which suggests that interaction of the response regulator with its cognate sensor kinase may require a region more extended than the REC domain. A T69S amino acid substitution in the REC domain of VanRst produced a strain exhibiting weak constitutive resistance, indicating that this particular amino acid may play a key role for VanS-independent phosphorylation in the response regulator protein.


CoLab: A workshop-based undergraduate research experience for entering college students.
The goal of undergraduate chemistry laboratories is to allow students to learn about chemical systems and key laboratory skills. They should then apply this knowledge to solve problems and connect macroscopic observations in the laboratory with those occurring at the submicroscopic level. Unfortunately, these needs are not met through traditional confirmation labs. Therefore, many chemistry instructors are turning towards research-based labs course-based undergraduate research experiences (CUREs). There are also many cases where summer workshops, often with non-traditional pedagogy, are used for students. This article describes the STEM CoLab Program, a novel type of summer workshop that seeks to build student chemistry knowledge and skills in research and presentation at the beginning of their college work. This program uses the principles of CUREs for students who are just entering the university, mostly as freshmen. Several different phenomena have been investigated during the program. In this paper, we report the overall work of the program from 2016 through 2021 and provide additional details on the program's implementation in 2020 and 2021 when students conducted their work from home, using a combination of a take home research kit for studying salivary amylase "in vitro" and computer-based visualizations of amylase-inhibitor interactions "in silico" using PyMOL and online docking tools.


Interstitial chemotherapy with biodegradable BCNU (Gliadel) wafers in the treatment of malignant gliomas.
Malignant gliomas represent the majority of primary brain tumors, and the prognosis of the patients afflicted with these tumors has been historically dismal, with almost uniform progressive neurologic impairment and rapid death. Even with multimodal treatment using surgery, focal radiation, and chemotherapy, no major strides were made until recently. The development of interstitial BCNU wafers (carmustine wafers, Gliadel((R))) has led to promising results in the treatment of a selected patients with malignant gliomas, as well as with other intracranial malignancies.BCNU is one of the first systemic chemotherapies which had obtained United States Food and Drug Administration (FDA) approval for the treatment of brain tumors. However, systemic use has been hampered by the modest prolongation of survival and by the prolonged myelosuppression and potentially fatal pulmonary toxicity. The development of interstitial therapies with BCNU represented a great step forward, allowing direct delivery to the tumor bed, with virtually no systemic toxicities. Clinical studies of BCNU wafers have showed good efficacy in both newly diagnosed and recurrent gliomas, as well as a possible therapeutic role in other primary or secondary intracranial malignancies. New studies are currently underway trying to improve the efficacy of the BCNU wafers (Gliadel((R))) by combining them with different systemic chemotherapies. An overview of the current knowledge ranging from the preclinical developments, to the efficacy and safety seen in the clinical trials and in clinical practice following the drug approval to the future avenues of research is therefore timely.


Use of Psychophysiological Portable Devices to Analyse Stress Response in Different Experienced Soldiers.
Previous studies have shown that actuate stress have a negative effect on working memory, visio-spatial ability and symptoms of disassociation. We conducted the present research with the aim of to analyse the effect of experience and training in psychophysiological response, attention and memory of soldiers in combat. Variables of blood lactate, blood glucose, blood oxygen saturation, body temperature, heart rate, lower body muscular strength manifestation, autonomic modulation, cortical arousal, cognitive and somatic anxiety, and memory by a post mission questionnaire were analysed before and after a combat simulation in 49 soldiers of Spanish Army. Combat simulation produced a significant increase (p < 0.05) in blood lactate, blood glucose, blood oxygen saturation, rated perceived exertion, heart rate, cognitive and somatic anxiety. Significant increase in low frequency domain and significant decrease in high frequency domain of the heart rate variability was found in experienced and highly trained soldiers. The percentage of correct response in the post mission questionnaire indicated that elements better remembered were those related with soldier integrity and considered as a possible life threat, Significant differences in the post mission questionnaire by experience and training was also found. Correlation analysis showed that higher psychophysiological activation correlated positively with cognitive impairment and lower memory. As a conclusion, higher experienced soldiers presented higher physiological activation as well as cognitive and memory impairment than lower experienced soldier after a combat simulation and memory function was modulated by the stimulus nature.


Population synchrony decreases with richness and increases with environmental fluctuations in an experimental metacommunity.
Fluctuations of local but connected populations may show correlation or synchrony whenever they experience significant dispersal or correlated environmental biotic and abiotic variability. Synchrony may be an important variable in multispecies systems, but its nature and implications have not been explicitly examined. Because the number of locally coexisting species (richness) affects the population variability of community members, we manipulated richness under different regimes of environmental fluctuation (EF). We predicted that the temporal synchrony of populations in a species should decline with increasing richness of the metacommunity they live in. Additionally, we predicted that specialist species that are sensitive to a specific environmental factor would show higher synchronization when EF increases. We thus created experimental communities with varied richness, EF, and species specialization to examine the synchronizing effects of these factors on three aquatic invertebrate species. We created four levels of richness and three levels of EF by manipulating the salinity of the culture media. Monocultures exhibited higher population synchrony than metacommunities of 2-4 species. Furthermore, we found that species responded differently to EF treatments: high EF enhanced population synchrony for the specialist and intermediate species, but not for the generalist species. Our findings emphasize that the magnitude of EF and species richness both contribute to determine population synchrony, and importantly, our results suggest that biotic diversity may actually stabilize metacommunities by disrupting synchrony.


Bicyclic Pyrrolidines for Medicinal Chemistry via [3 + 2]-Cycloaddition.
A general approach to bicyclic fused pyrrolidines via [3 + 2]-cycloaddition between nonstabilized azomethyne ylide and endocyclic electron-deficient alkenes was elaborated. "Push-pull" alkenes and CF3-alkenes did not react with the azomethyne ylide under the previously reported conditions, and we developed a superior protocol (LiF, 140 °C, no solvent). Among obtained products were medchem-relevant bicyclic sulfones, monofluoro-, difluoro-, and trifluoromethyl-substituted pyrrolidines. This approach not only allowed preparation of novel molecules but also significantly simplified synthesis of the existing ones (e.g., sofinicline).


theLiTE™: A Screening Platform to Identify Compounds that Reinforce Tight Junctions.
Tight junctions (TJ) are formed by transmembrane and intracellular proteins that seal the intercellular space and control selective permeability of epithelia. Integrity of the epithelial barrier is central to tissue homeostasis and barrier dysfunction has been linked to many pathological conditions. TJ support the maintenance of cell polarity through interactions with the Par complex (Cdc42-Par-6-Par-3-aPKC) in which Par-6 is an adaptor and links the proteins of the complex together. Studies have shown that Par-6 overexpression delays the assembly of TJ proteins suggesting that Par-6 negatively regulates TJ assembly. Because restoring barrier integrity is of key therapeutic and prophylactic value, we focus on finding compounds that have epithelial barrier reinforcement properties; we developed a screening platform (theLiTE™) to identify compounds that modulate Par-6 expression in follicular epithelial cells from Par-6-GFP Drosophila melanogaster egg chambers. Hits identified were then tested whether they improve epithelial barrier function, using measurements of transepithelial electrical resistance (TEER) or dye efflux to evaluate paracellular permeability. We tested 2,400 compounds, found in total 10 hits. Here we present data on six of them: the first four hits allowed us to sequentially build confidence in theLiTE™ and two compounds that were shortlisted for further development (myricetin and quercetin). We selected quercetin due to its clinical and scientific validation as a compound that regulates TJ; food supplement formulated on the basis of this discovery is currently undergoing clinical evaluation in gastroesophageal reflux disease (GERD) sufferers.


Cost-related medication nonadherence in Canada: a systematic review of prevalence, predictors, and clinical impact.
Cost-related nonadherence to medications (CRNA) is common in many countries and thought to be associated with adverse outcomes. The characteristics of CRNA in Canada, with its patchwork coverage of increasingly expensive medications, are unclear. Our objective in this systematic review was to summarize the literature evaluating CRNA in Canada in three domains: prevalence, predictors, and effect on clinical outcomes. We searched MEDLINE, Embase, Google Scholar, and the Cochrane Library from 1992 to December 2019 using search terms covering medication adherence, costs, and Canada. Eligible studies, without restriction on design, had to have original data on at least one of the three domains specifically for Canadian participants. Articles were identified and reviewed in duplicate. Risk of bias was assessed using design-specific tools. Twenty-six studies of varying quality (n = 483,065 Canadians) were eligible for inclusion. Sixteen studies reported on the overall prevalence of CRNA, with population-based estimates ranging from 5.1 to 10.2%. Factors predicting CRNA included high out-of-pocket spending, low income or financial flexibility, lack of drug insurance, younger age, and poorer health. A single randomized trial of free essential medications with free delivery in Ontario improved adherence but did not find any change in clinical outcomes at 1 year. CRNA affects many Canadians. The estimated percentage depends on the sampling frame, the main predictors tend to be financial, and its association with clinical outcomes in Canada remains unproven.


A social marketing approach to changing mental health practices directed at youth and adolescents.
The mental health problems of children are of increasing social concern. Many best practices have been developed but often not implemented. Social marketing has been suggested as an innovative, useful approach to this challenge-along with others in the health care field. However, much confusion exists over what the approach entails, where it has been applied and how it can be adapted to significant social challenges such as changing mental health practices directed at youth and adolescents. This article defines key terms, offers historical perspective and provides a specific approach and set of models to implement an effective social marketing strategy in a range of contexts.


Molecular marker dissection of stem rust resistance in Nebraska bread wheat germplasm.
Stem rust (caused by Puccinia graminis f. sp. tritici) is a major disease of wheat. To understand the genetic basis of stem rust resistance in Nebraska winter wheat, a set of 330 genotypes representing two nurseries (DUP2015 and TRP2015) were evaluated for resistance to a Nebraska stem rust race (QFCSC) in two replications. The TRP2015 nursery was also evaluated for its resistance to an additional 13 stem rust races. The analysis of variance revealed significant variation among genotypes in both populations for stem rust resistance. Nine stem rust genes, Sr6, Sr31, Sr1RSAmigo, Sr24, Sr36, SrTmp, Sr7b, Sr9b, and Sr38, were expected and genotyped using gene-specific markers. The results of genetic analysis confirmed the presence of seven stem rust resistance genes. One genotype (NE15680) contained target alleles for five stem rust resistance genes and had a high level of stem rust resistance against different races. Single marker analysis indicated that Sr24 and Sr38 were highly significantly associated with stem rust resistance in the DUP2015 and TRP2015 nurseries, respectively. Linkage disequilibrium analysis identified the presence of 17 SNPs in high linkage with the Sr38-specific marker. These SNPs potentially tagging the Sr38 gene could be used in marker-assisted selection after validating them in additional genetic backgrounds.


Antibody responses after inactivated influenza vaccine in young children.
The frequency and duration of antibody responses after trivalent inactivated influenza vaccine (TIV) in young children are not well defined and assume greater importance with the expanded recommendations for vaccine use in children aged 6 months-5 years. Forty-three children aged 6-23 months were vaccinated with TIV in the fall of 2002. At enrollment the majority of children were seronegative to one or more of the vaccine antigens and had no previously documented influenza. Postvaccination sera were collected in the subsequent fall and winter seasons. Acute antibody responses to TIV were determined using standardized hemagglutination inhibition (HAI) and neutralization assays. In calculating the duration of responses, sequential sera were analyzed to the last available sera, to the point at which antibody became undetectable, or to intercurrent influenza infection. Forty-three subjects contributed 121 sera that were analyzed for HAI responses to TIV. Four-fold HAI rises after 2 doses of TIV in naive individuals were seen in 13 (72%) to H3N2, 22 (92%) to H1N1, and 15 (60%) to influenza B. Fewer 4-fold rises were seen in those with preexisting antibody. The results of microneutralization assays to H3N2 correlated well with HAI results. The time for antibody to decay to one-half of the postvaccination titer (t1/2) was approximately 126 days for H1N1 and 258 days for H3N2. Although not all children responded with 4-fold rises in antibody or achieved the putative protective titer of > or =1:32, the half-life of antibody suggested that children immunized in the fall should have immune responses sustained throughout the ensuing influenza season.


Misclassification of coronary heart disease in mortality statistics. Evidence from the WHO-MONICA Ghent-Charleroi Study in Belgium.
To validate the Belgian vital statistics for coronary heart disease (CHD) on the basis of an independent acute myocardial infarction (AMI) register, carried out as part of the WHO-MONICA project. Records of fatal cases of AMI in the WHO-MONICA register were individually linked to the corresponding death certificates. Since 1983, the WHO-MONICA Collaborating Centre Ghent/Charleroi registers all fatal and non-fatal AMI in the age group 25-69 years in two geographical areas, Ghent in the northern Dutch speaking part and Charleroi in the southern French speaking part of Belgium. Registration is done according to the MONICA protocol. The official vital statistics in Belgium are published on a yearly basis. They are essentially a reflection of the "underlying" causes of death, coded according to the 9th revision of the International Classification of Diseases (ICD). The study was undertaken in the period 1983-1991. Out of a total of 741 (Ghent) and 934 (Charleroi) well documented MONICA fatal cases of AMI, 492 (66.4%) and 641 (68.6%), respectively, were officially labelled as CHD (ICD code 410-414); 438 (59.1%) and 385 (41.2%), respectively, were officially labelled as AMI (ICD code 410). A substantial fraction of the MONICA AMI cases--27.1% in Ghent and 38.2% in Charleroi--was coded as "other forms of CHD" (ICD 411-414) or as "other forms of heart disease" (ICD 420-429). The remaining MONICA AMI cases--13.8% in Ghent and 20.6% in Charleroi--were classified in either very aspecific (for example, atherosclerosis, ICD 440) or totally unrelated ICD codes (for example, neoplasm, ICD 140-239). It is concluded from the results in this paper that a substantial part of all deaths caused by CHD in Belgium are labelled with incorrect ICD codes and are therefore misclassified in the official mortality statistics for Belgium. This is partly caused by a "drainage" of cases towards less specific CHD related ICD categories. A considerable fraction, however, seems to be absolutely misclassified.


Patient-centeredness in psychiatric work disability evaluations and the reproducibility of work capacity estimates.
To evaluate the extent of patient-centeredness in psychiatric work disability evaluations and its association with the reproducibility of work capacity (WC) estimates. In our mixed methods study, 29 video-taped interviews conducted in psychiatric work disability evaluations were coded with the Roter Interaction Analysis System (RIAS) and different measures of patient-centeredness were derived from these codings, including a summary patient-centred communication ratio. Four experts each estimated a claimant's WC on a scale from 0% to 100%. Patient-centred communication ratios were always >1, suggesting a preponderance of psychosocial information exchange. In contrast, utterances reflecting empathy were rare e.g., the expert did not address the claimant's emotions in 25 of 29 interviews. None of the derived patient-centeredness measures showed a significant association with WC reproducibility. Many of the experts' questions addressed the claimant's lifestyle and psychosocial situation. However, this likely reflected factual requirements for the expert opinion, rather than patient-centeredness. Indeed, the experts rarely showed empathy, which is a hallmark characteristic of patient-centeredness. The reproducibility of work capacity estimates was not modulated by patient-centeredness, irrespective of its quantification. Patient-centeredness in work disability evaluations should find its entry in continuing education of experts.


Outcomes of transanal total mesorectal excision compared to laparoscopic total mesorectal excision: A meta-analysis of randomized controlled trials.
Transanal dissection is increasingly used in laparoscopic surgery for total mesorectal excision of lower rectal cancers. Several studies compared outcomes of laparoscopic total mesorectal excision with and without transanal dissection, yet there is a paucity of high-quality evidence. This meta-analysis aimed to provide a pooled comparative analysis of outcomes of laparoscopic total mesorectal excision with and without transanal dissection based on evidence from randomized controlled trials. This Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2022-compliant systematic review of randomized controlled trials compared laparoscopic total mesorectal excision with and without transanal dissection. PubMed, Scopus, and Web of Science were searched through March 2023. The Medical Subject Headings terms used in the search were Rectal neoplasms, Proctectomy, Laparoscopy, and Transanal. The main outcomes included operative and pathologic outcomes. The risk of bias was assessed using the Risk of Bias version 2 tool, and certainty of the evidence was graded using the Grading of Recommendations Assessment, Development, and Evaluation approach. The primary study outcome was conversion to open surgery. Four randomized controlled trials (1,339 patients; median age 61.2 years) were included; 671 patients underwent laparoscopic total mesorectal excision with transanal dissection, and 668 underwent laparoscopic total mesorectal excision without transanal dissection. Both groups were similar in age, body mass index, and disease stage, but the laparoscopic total mesorectal excision with transanal dissection group had a higher male-to-female ratio, received neoadjuvant therapy and had a hand-sewn anastomosis more often. Patients who underwent laparoscopic total mesorectal excision with transanal dissection had lower conversion rates (odds ratio = 0.179; P = .001), a higher likelihood of achieving complete total mesorectal excision (odds ratio = 1.435; P = .025), and fewer harvested lymph nodes (weighted mean difference = -1.926; P = .035). The groups had similar operative times (weighted mean difference = -3.476; P = .398), total complications (odds ratio = 0.94; P = .665), major complications (odds ratio = 1.112; P = .66), anastomotic leak (odds ratio = 0.67; P = .432), positive circumferential resection margin (odds ratio = 0.549; P = .155), and positive distal margins (odds ratio = 0.559; P = .171). Laparoscopic total mesorectal excision with transanal dissection was associated with lower odds of conversion to open surgery, greater likelihood of achieving complete total mesorectal excision, and fewer harvested lymph nodes than laparoscopic total mesorectal excision without transanal dissection.


Lethal genes surviving by mosaicism: a possible explanation for sporadic birth defects involving the skin.
A genetic concept is advanced to explain the origin of several sporadic syndromes characterized by a mosaic distribution of skin defects. It is postulated that these disorders are due to the action of a lethal gene surviving by mosaicism. The presence of the mutation in the zygote will lead to death of the embryo at an early stage of development. Cells bearing the mutation can survive only in a mosaic state, in close proximity with normal cells. The mosaic may arise either from a gametic half chromatid mutation or from an early somatic mutation. This concept of origin is proposed to apply to the Schimmelpenning-Feuerstein-Mims syndrome, the McCune-Albright syndrome, the Klippel-Trenaunay syndrome, the Sturge-Weber syndrome, and neurocutaneous melanosis. Moreover, this etiologic hypothesis may apply to two other birth defects that have recently been delineated, the Proteus syndrome (partial gigantism of hands or feet, hemihypertrophy, macrocephaly, linear papillomatous epidermal nevus, subcutaneous hemangiomas and lipomas, accelerated growth, and visceral anomalies), and the Delleman-Oorthuys syndrome (orbital cyst, porencephaly, periorbital appendages, and focal aplasia of the skin.


SU5416 plus interferon alpha in advanced renal cell carcinoma: a phase II California Cancer Consortium Study with biological and imaging correlates of angiogenesis inhibition.
Vascular endothelial growth factor (VEGF) is expressed in up to 70% of renal cell carcinomas (RCCs) and is a rational therapeutic target. SU5416 is a small molecule inhibitor of VEGF-mediated signaling through Flk-1, a transmembrane tyrosine kinase. IFN-alpha also possesses dose- and schedule-dependent antiangiogenic effects at doses lower than those used for RCC therapy. We hypothesized that SU5416 plus low dose IFN-alpha 2B (Intron-A) would result in a 1-year event-free survival (EFS), exceeding 20% in patients with metastatic RCC using the results of a randomized immunotherapy trial as historical control. Efficacy was correlated with serial plasma VEGF and plasminogen activator inhibitor-1 levels and with positron emission tomography scans. Thirty patients were treated with SU5416 145 mg/m(2) i.v. twice weekly plus Intron-A 1 million units s.c. twice daily, cycled every 6 weeks. Fifteen patients (50%) had stable disease (SD) at 12 weeks, including 1 minor response and 8 with progressive disease (27%). Median survival time was 10 months, and 1-year EFS was 6% (95% confidence interval, 1-35). The most common grade 3 or 4 toxicities included fatigue and lymphopenia, among others. There were 3 on-study deaths, 2 of which were infection-related. Significant declines in median plasma levels of VEGF pre- and posttherapy were observed. In 5 patients with paired FDG and O-15 positron emission tomography scans, tumor metabolism and perfusion were unchanged in 3 patients with SD, increased in 1 patient with progression, and decreased in 1 patient with SD. Although SU5146 plus low-dose IFN exhibits biological activity in RCC as evidenced by significant declines in serial VEGF and plasminogen activator inhibitor-1 plasma levels, the 1-year EFS of 6% and adverse toxicity profile diminishes enthusiasm for additional studies with this combination in advanced RCC.


Quantification of Thread Engagement in Screw-Plate Interface of Polyaxial Locking System Using X-ray Computed Tomography.
This study demonstrates a new method for quantifying thread engagement in mechanical connections and verifies its applicability using biomedical implants under push-out tests. The focus is on orthopedic plate implants employed for bone fracture fixation, which, by design, allow off-axis screw insertion to accommodate different contact conditions. Thread engagement is crucial in determining connection strength and stability. In medical practice, off-axis screw placement is usually necessary due to bone geometries and implant plate rigidity. To address this, the study proposes a quantification method using non-destructive testing with X-ray micro-computed tomography and automated image processing, although tuning the image processing parameters is vital for accurate and reliable results. This enables detailed 3D models of screw-plate interfaces for precise thread engagement measurement. The results show that thread engagement decreases with both, increased off-axis insertion angles and higher torque during insertion. Correlation analysis reveals a strong relationship (R2 > 0.6) between average thread engagement and push-out strength, underscoring the importance of proper screw placement for stable fixation.


Cost analysis of a simulation-based training for health workforce in India.
Training of health-care workforce including doctors, staff nurses, and Auxiliary Nurse Midwives using simulation techniques for skill enhancement have been used in a variety of clinical settings to improve the quality of training. India adopted the skills laboratories model for capacity building of health workers in maternal and child health in Bihar state. Current economic evaluation was performed with the objective of assessing the financial and economic cost of implementing skills laboratories. Data on all resources spent for the development of skill laboratory and implementing training during financial year 2011 were collected from Patna district in Bihar state. We used standard methods to estimate the full financial and economic costs of implementing the skills laboratories from a health system perspective. Overall cost of implementing 20 permanent and 10 mobile skills laboratory training in Bihar was Indian Rupee (INR) 8849895 from a financial perspective. The cost was nearly two times higher when using an economic perspective to account for opportunity cost of all resources used. The unit cost of training a participant using permanent and mobile laboratory was INR 6856 and INR 7474, respectively assuming an annual volume of 90 training. The optimum number of training which should be operated annually in a skills laboratory to make it most efficient is about 70-80 training per annum. Economic implications of skills laboratory organization should be borne while planning scale up in Bihar and other states. Further research on the effectiveness of two models of skill laboratory, that is, permanent and mobile and their cost is recommended.


Successful management of gastrointestinal haemorrhage associated with ischaemic colonic ulceration in acute pancreatitis with video assisted retroperitoneal debridement.
Colonic involvement is an uncommon but potentially lethal complication of severe acute pancreatitis and has received little attention in the surgical literature. Such complications can range from localized colonic pathology to widespread ischaemic pancolitis. Treatment options have historically been limited to resection of the affected segment. We describe the successful role of video assisted retroperitoneal pancreatic debridement in the management of two cases presenting with major gastrointestinal haemorrhage due to localised colonic ulceration on the background of acute necrotising pancreatitis. Video assisted retroperitoneal debridement should be considered early in the management of local colonic complications associated with severe acute necrotising pancreatitis.


Photooxidative destruction of chloroplasts and its consequences for cytosolic enzyme levels and plant development.
Mustard (Sinapis alba L.) seedlings were grown in the presence of herbicides (Difunon, Norflurazon) which inhibit carotenoid synthesis without affecting development, in darkness or in continuous far-red light. In strong white light (12,000 lx) the cotyledons of the herbicide-treated seedlings did not contain normal chloroplasts, but only small chlorophyll-free rudiments whose internal structure had almost disappeared. The plastid marker enzyme NADP-dependent glyceraldehyde-3-phosphate dehydrogenase was almost lacking. Plastid ribosomes and ribosomal RNAs were no longer detectable nor could synthesis of mature plastidal ribosomal RNAs be detected. Cytosolic ribosomes and rRNAs were not affected. Plastid DNA was apparently still intact as shown by restriction analysis. The appearance of marker enzymes of glyoxisomes, mitochondria and cytosol was not impaired while the level of marker enzymes of peroxisomes was drastically lowered. Accumulation of anthocyanin in mustard cotyledons was normal after a short, transient delay. Levels of representative enzymes of flavonoid biogenesis (phenylalanine ammonia-lyase, chalcone synthase) were somewhat increased rather than inhibited in the cotyledons of herbicide-treated, white-light-grown seedlings. The growth rate of hypocotyl and cotyledons was inhibited to the same extent in the herbicide-treated, white-light-grown seedling, although light inhibits growth of hypocotyls and promotes growth of cotyledons. Analysis of the data shows that photomorphogenesis of a herbicide-treated, white-light-grown seedling is normal, and is thus independent of plastid gene expression However, a 'factor' which coacts multiplicatively with phytochrome in determining the growth rate of the organs seems to originate from the plastids. Biogenesis of anthocyanin and synthesis of major enzymes of the flavonoid pathway are not affected adversely by a photooxidative elimination of plastid gene expression.


The potential of soybean phytoestrogens for postmenopausal hormone replacement therapy.
Hormone replacement therapy for postmenopausal women greatly reduces their risk of coronary heart disease. However, current pharmaceutical regimens have a low acceptance rate among postmenopausal women. We have sought to identify an alternative treatment that would retain the beneficial health effects of current standard therapy without its negative aspects. We have concentrated our research on naturally occurring estrogens (called phytoestrogens) found in soybeans, in the belief that delivery of phytoestrogens via the diet would be more acceptable than pharmaceutical regimens. Using a well-established nonhuman primate model of postmenopausal women, we have investigated the effects of soy phytoestrogens on cardiovascular risk factors and the reproductive system. In this review, we summarize the results of our ongoing research.


Mechanism of initiation and regulation of axonal degeneration with special reference to NMNATs and Sarm1.
Axonal degeneration is observed in a variety of contexts in both the central and peripheral nervous systems. Pathological signaling to regulate the progression of axonal degeneration has long been studied using Wallerian degeneration, the prototypical axonal degradation observed after injury, as a representative model. Understanding metabolism of nicotinamide adenine dinucleotide (NAD+) and the functional regulation of Sarm1 has generated great progress in this field, but there are a number of remaining questions. Here, in this short review, we describe our current understanding of the axonal degeneration mechanism, with special reference to the biology related to wlds mice and Sarm1. Furthermore, variations of axonal degeneration initiation are discussed in order to address the remaining questions needed for mechanistic clarification.


Type 1 fimbriae of Salmonella enterica serovar Typhimurium bind to enterocytes and contribute to colonization of swine in vivo.
Salmonella enterica serovar Typhimurium strain 798 is a clinical isolate from a pig and is known to be able to cause persistent, asymptomatic infections. This strain also is known to exist in two phenotypes (adhesive and nonadhesive to enterocytes) and can switch between the two phenotypes at a rate consistent with phase variation. Cells in the adhesive phenotype are more readily phagocytosed by leukocytes than nonadhesive cells. Once in a leukocyte, adhesive-phase cells survive while nonadhesive-phase cells die. In the present study, nonadhesive mutants were obtained with the transposon TnphoA. A nonadhesive mutant was selected for study and was shown by electron microscopy not to produce fimbriae. The gene encoding the adhesin was cloned and sequenced. Based on its sequence, the adhesin was shown to be FimA, the major subunit of type 1 fimbriae. The nonadhesive mutant was attenuated in its ability to colonize both mouse and pig intestines, but remained capable of systemic spread in mice. The nonadhesive mutant was phagocytosed to the same extent as parental cells in the adhesive phase and then survived intracellularly. These results demonstrated that type 1 fimbriae were important for attachment to enterocytes and promoted intestinal colonization. However, they were not important in promoting phagocytosis or intracellular survival.


Acute mastoiditis in Greenland between 1994-2007.
The indigenous populations of the Arctic are prone to middle ear infections starting with an early age first episode, followed by frequent episodes of acute otitis media (AOM) during childhood. A high proportion develop chronic otitis media. Acute mastoiditis is a serious complication of AOM in childhood with postauricular swelling, erythema, and tenderness, protrusion of the auricle, high fever and general malaise. The disease may protrude intracranially. The incidence rates for acute mastoiditis in the Western world range from 1.2 to 4.2 cases/100 000 per year. There exists no epidemiological data on acute mastoiditis in the Arctic region. A retrospective search was made for the WHO ICD-10 code DH70.0 (denoting acute mastoiditis) using the National Greenland Inpatient Register for the period 1994-2007, inclusive. Fifteen patients were registered and their medical records were retrieved. Four patients were obviously misclassified, leaving 11 patients for evaluation. The medical records were available for 10 patients. The diagnostic inclusion criterion was written clinical signs of acute mastoiditis. Based on the case series the incidence rate was calculated to be 1.4 for the total Greenlandic population and 7.4 for children 0 and 10 years of age. Median age was 14 months (5-105 months) and eight were female (72%). Seven of the 10 were exclusively treated with antibiotics and three underwent additional ear surgery. Bacteriological examination was performed in five of 10. One 8 month-old girl presented with a contemporary facial nerve paralysis and was treated with intravenous antibiotics; one 8 year-old girl was evacuated to Copenhagen for urgent surgery due to signs of meningitis. Acute CT scan showed a cerebellar abscess and a thrombosis in the lateral sigmoid sinus vein. An extensive cholesteatoma was found and eradicated during surgery. Six weeks later the patient returned home with a maximal conductive hearing loss as the only complication. All patients recovered from the disease. The incidence of acute mastoiditis in Greenland is comparable to the incidence elsewhere, although AOM occurs more frequently among small children in the Greenlandic population. The disease is serious and must be treated immediately with intravenous antibiotics, followed by urgent surgery if there is no improvement.


China's limited push model of FOI legislation.
China has adopted a push model of Freedom of Information (FOI) legislation that emphasizes proactive disclosure of government information. This differs from a pull model that stresses citizen-initiated access or reactive disclosure. The push model of FOI legislation, which has reduced the importance of access requests in China, grew out of its local causes. However, the degree of push or proactive disclosure under China's current FOI Regulations is undermined by several factors, including a limited access mechanism, broad and vague exemptions, and the omission of the maximum disclosure principle.


Italian multicentre study on type A acute aortic dissection: a 33-year follow-up†.
Despite substantial progress in surgical techniques and perioperative management, the treatment and long-term follow-up of type A acute aortic dissection (AAD) still remain a major challenge. The objective of this retrospective, multicentre study was to assess in a large series of patients the early and long-term results after surgery for type A AAD. We analysed the preoperative, intraoperative and postoperative conditions of 1.148 consecutive patients surgically treated in seven large referral centres from 1981 to 2013. We applied to each patient three different multi-parameter risk profiles (preadmission risk, admission risk and post-surgery risk) in order to compare risk factors and outcome. Long-term Kaplan-Meier survival was evaluated. The median age was 64 years and the male population was predominant (66%). Identified diagnosis of collagen disease was present in 9%, and Marfan syndrome in 5%. Bicuspid aortic valve was present in 69 patients (6%). Previous cardiac surgery was identified in 10% of the patients. During surgery, the native aortic valve was preserved in 72% of the cases, including leaflet resuspension in 23% and David operation in 1.2%. Considering aortic valve replacement (AVR: 28%), bioprosthesis implantation was performed in 14.7% of the subjects. Neurological impairment at discharge was shown in 23% of the cases among which 21% of patients had new neurological impairment versus preoperative conditions. The overall 30-day mortality rate was 25.7%. All risk profiles remained independently associated with in-hospital mortality. During the available follow-up of hospital survivors (median: 70 months, interquartile range: 34-113, maximum: 396), cardiac-related death occurred in 7.9% of the subjects. The cumulative survival rate for cardiac death was 95.3% at 5 years, 92.8% at 10 years and 52.8% at 20 years. Severe aortic regurgitation (AR) (grade 3-4) at the time of surgery showed to be a significant risk factor for reintervention during the follow-up (P < 0.001). Among risk profiles, only the preadmission risk was independently associated with late mortality after multivariate analysis. Unexpectedly, there was no difference in freedom from cardiac death between patients with and without AVR. Although surgery for type A has remained challenging over more than three decades, there is a positive trend in terms of hospital mortality and long-term follow-up. About 90% of patients were free from reoperation in the long term, although late AR remains a critical issue, suggesting that a thorough debate on surgical options, assessment and results of a conservative approach should be considered.


[Analysis of tuberculosis quality diagnosis by autopsy data].
The records of autopsies and history cases of deceased patients served as a material for analyzing the quality of clinical diagnosis of tuberculosis in 1987-1997. A hundred and eighty and six patients (39.1%) were autopsied. Of them 139 (74.7%) and 47 (25.3%) died from tuberculosis and other diseases, respectively. Tuberculosis and its complications were recognized in 113 (81.3%) patients during their life. Fibrocavernous tuberculosis was a prevalent clinical form in 104 (55.9%) of the deceased. Progressive tuberculosis, more commonly as complications of cavernous tuberculosis (in 49 (35.2%) patients) and those of hematogenic generalization (in 23 (16.5%)) were a direct cause of death in most tuberculosis patients (n = 72 (51.8%)).


Night Watch in One Brain Hemisphere during Sleep Associated with the First-Night Effect in Humans.
We often experience troubled sleep in a novel environment [1]. This is called the first-night effect (FNE) in human sleep research and has been regarded as a typical sleep disturbance [2-4]. Here, we show that the FNE is a manifestation of one hemisphere being more vigilant than the other as a night watch to monitor unfamiliar surroundings during sleep [5, 6]. Using advanced neuroimaging techniques [7, 8] as well as polysomnography, we found that the temporary sleep disturbance in the first sleep experimental session involves regional interhemispheric asymmetry of sleep depth [9]. The interhemispheric asymmetry of sleep depth associated with the FNE was found in the default-mode network (DMN) involved with spontaneous internal thoughts during wakeful rest [10, 11]. The degree of asymmetry was significantly correlated with the sleep-onset latency, which reflects the degree of difficulty of falling asleep and is a critical measure for the FNE. Furthermore, the hemisphere with reduced sleep depth showed enhanced evoked brain response to deviant external stimuli. Deviant external stimuli detected by the less-sleeping hemisphere caused more arousals and faster behavioral responses than those detected by the other hemisphere. None of these asymmetries were evident during subsequent sleep sessions. These lines of evidence are in accord with the hypothesis that troubled sleep in an unfamiliar environment is an act for survival over an unfamiliar and potentially dangerous environment by keeping one hemisphere partially more vigilant than the other hemisphere as a night watch, which wakes the sleeper up when unfamiliar external signals are detected.


Methods for Improving Representativeness in a Web Survey on Sexual Assault Among College Students.
Many colleges and universities conduct web-based campus climate surveys to understand the prevalence and nature of sexual assault among their students. When designing and fielding a web survey to measure a sensitive topic like sexual assault, methodological decisions, including the length of the field period and the use or amount of an incentive, can affect the representativeness of the respondent sample leading to biased or imprecise estimates. This study uses data from the Campus Climate Survey Validation Study (CCSVS) to assess how the interaction between field period length and survey incentive amount affects nonresponse, sample representativeness, and the precision of survey estimates. Research suggests that using robust incentives gives potential survey respondents a reason to complete the survey beyond their intrinsic motivation to do so. Likewise, extending the field period gives more time to people who may be less intrinsically motivated to complete the survey. Both serve to increase sample size and representativeness, minimize bias, and improve estimate precision. Schools, however, sometimes lack the time and/or resources for both a robust incentive and a lengthy field period, and this study examines the extent to which the potential negative impacts of not using one can be mitigated by the presence of the other. Findings indicate that target response rates can be achieved using a smaller incentive if the field period is lengthy but, even with a lengthy field period, the use of a smaller incentive can result in biased estimates due to a lack of representativeness. Conversely, when a robust incentive is used and weights are developed to adjust for nonresponse, a shorter field period will not have a significant impact on point estimates, but the estimates will be less precise due to fewer respondents participating in the survey.


Molecular scale contact line hydrodynamics of immiscible flows.
From extensive molecular dynamics simulations on immiscible two-phase flows, we find the relative slipping between the fluids and the solid wall everywhere to follow the generalized Navier boundary condition, in which the amount of slipping is proportional to the sum of tangential viscous stress and the uncompensated Young stress. The latter arises from the deviation of the fluid-fluid interface from its static configuration. We give a continuum formulation of the immiscible flow hydrodynamics, comprising the generalized Navier boundary condition, the Navier-Stokes equation, and the Cahn-Hilliard interfacial free energy. Our hydrodynamic model yields interfacial and velocity profiles matching those from the molecular dynamics simulations at the molecular-scale vicinity of the contact line. In particular, the behavior at high capillary numbers, leading to the breakup of the fluid-fluid interface, is accurately predicted.


Effect of drug treatment changes and seizure outcomes on depression and suicidality in adults with drug-resistant focal epilepsy.
To investigate changes in depressive and suicidality status and their relationship with seizure outcomes after addition or substitution of another antiseizure medication (ASM) in adults with drug-resistant focal epilepsy. 770 consecutively enrolled patients were assessed and followed prospectively for seizure outcome and depressive status over a 6-month period after starting treatment with a newly introduced ASM. The Neurological Disorders Depression Inventory for Epilepsy (NDDIE) was used to screen for depression and suicidality. Correlations of NDDIE results with clinical and treatment-related variables were assessed by using a stepwise logistic regression model. At baseline, 50.0% of patients had a positive screening test result for depression and 13.0% had a positive screening test result for suicidal ideation. A psychiatric comorbidity at baseline was associated with a 2.3 times increased risk of an initially negative NDDIE screening result becoming positive at re-assessment after 6 months. Number of ASMs taken at baseline also correlated with an increased risk of a change in depression screening test results from negative to positive during follow-up, whereas no association was identified with sociodemographic and epilepsy-related variables, including seizure outcomes. Approximately 6% of patients initially negative at screening for suicidal ideation became positive at the 6-month re-assessment. The risk of switch from a negative to a positive screening test result for suicidal ideation was increased more than two-fold in individuals who screened positive for depression at baseline, and was unrelated to type of ASM introduced, sociodemographic variables or seizure outcomes. Almost 1 in 5 adults with drug resistant focal epilepsy who screen negative for depression become positive when re-assessed 6 months after a treatment change. 6.1% who screen initially negative for passive suicidal ideation become positive at re-assessment 6 months later. These changes in screening status are independent of type of ASM introduced or seizure outcomes, but correlate with psychiatric status at baseline.


Sumoylation of hypoxia-inducible factor-1α ameliorates failure of brain stem cardiovascular regulation in experimental brain death.
One aspect of brain death is cardiovascular deregulation because asystole invariably occurs shortly after its diagnosis. A suitable neural substrate for mechanistic delineation of this aspect of brain death resides in the rostral ventrolateral medulla (RVLM). RVLM is the origin of a life-and-death signal that our laboratory detected from blood pressure of comatose patients that disappears before brain death ensues. At the same time, transcriptional upregulation of heme oxygenase-1 in RVLM by hypoxia-inducible factor-1α (HIF-1α) plays a pro-life role in experimental brain death, and HIF-1α is subject to sumoylation activated by transient cerebral ischemia. It follows that sumoylation of HIF-1α in RVLM in response to hypoxia may play a modulatory role on brain stem cardiovascular regulation during experimental brain death. A clinically relevant animal model that employed mevinphos as the experimental insult in Sprague-Dawley rat was used. Biochemical changes in RVLM during distinct phenotypes in systemic arterial pressure spectrum that reflect maintained or defunct brain stem cardiovascular regulation were studied. Western blot analysis, EMSA, ELISA, confocal microscopy and immunoprecipitation demonstrated that drastic tissue hypoxia, elevated levels of proteins conjugated by small ubiquitin-related modifier-1 (SUMO-1), Ubc9 (the only known conjugating enzyme for the sumoylation pathway) or HIF-1α, augmented sumoylation of HIF-1α, nucleus-bound translocation and enhanced transcriptional activity of HIF-1α in RVLM neurons took place preferentially during the pro-life phase of experimental brain death. Furthermore, loss-of-function manipulations by immunoneutralization of SUMO-1, Ubc9 or HIF-1α in RVLM blunted the upregulated nitric oxide synthase I/protein kinase G signaling cascade, which sustains the brain stem cardiovascular regulatory machinery during the pro-life phase. We conclude that sumoylation of HIF-1α in RVLM ameliorates brain stem cardiovascular regulatory failure during experimental brain death via upregulation of nitric oxide synthase I/protein kinase G signaling. This information should offer new therapeutic initiatives against this fatal eventuality.


Genomic patterns and characterizations of chromosomally-encoded mcr-1 in Escherichia coli populations.
The emergence and transmission of the mobile colistin resistance gene (mcr-1) threatened the extensive use of polymyxin antimicrobials. Accumulated evidence showed that the banning of colistin additive in livestock feed efficiently reduce mcr-1 prevalence, not only in animals but also in humans and environments. However, our previous study has revealed that a small proportion of Escherichia coli could continually carry chromosomally-encoded mcr-1. The chromosomally-encoded events, indicated the existence of stabilized heritage of mcr-1 and revealed a potential threat in the antimicrobial stewardship interventions, are yet to be investigated. In this study, we systematically investigated the genetic basis of chromosomally-encoded mcr-1 in prevalence and potential mechanisms of lineage, plasmid, insertion sequence, and phage. Our results demonstrated that the emergence of chromosomally-encoded mcr-1 could originate from multiple mechanisms, but mainly derived through the recombination of ISApl1/Tn6330. We reported a specific transmission mechanism, which is a phage-like region without lysogenic components, could associate with the emergence and stabilization of chromosomally-encoded mcr-1. These results highlighted the potential origin and risks of chromosomally-encoded mcr-1, which could be a heritable repository and thrive again when confronted with new selective pressures. To the best of our knowledge, this is the first study to systematically reveal the genomic basis of chromosomally-encoded mcr-1, and report a specific transmission pattern involved in phage-like region. Overall, we demonstrate the origin mechanisms and risks of chromosomally-encoded mcr-1. It highlights the need of public attention on chromosome-encoded mcr-1 to prevent from its reemergence.


Passive dendrites enable single neurons to compute linearly non-separable functions.
Local supra-linear summation of excitatory inputs occurring in pyramidal cell dendrites, the so-called dendritic spikes, results in independent spiking dendritic sub-units, which turn pyramidal neurons into two-layer neural networks capable of computing linearly non-separable functions, such as the exclusive OR. Other neuron classes, such as interneurons, may possess only a few independent dendritic sub-units, or only passive dendrites where input summation is purely sub-linear, and where dendritic sub-units are only saturating. To determine if such neurons can also compute linearly non-separable functions, we enumerate, for a given parameter range, the Boolean functions implementable by a binary neuron model with a linear sub-unit and either a single spiking or a saturating dendritic sub-unit. We then analytically generalize these numerical results to an arbitrary number of non-linear sub-units. First, we show that a single non-linear dendritic sub-unit, in addition to the somatic non-linearity, is sufficient to compute linearly non-separable functions. Second, we analytically prove that, with a sufficient number of saturating dendritic sub-units, a neuron can compute all functions computable with purely excitatory inputs. Third, we show that these linearly non-separable functions can be implemented with at least two strategies: one where a dendritic sub-unit is sufficient to trigger a somatic spike; another where somatic spiking requires the cooperation of multiple dendritic sub-units. We formally prove that implementing the latter architecture is possible with both types of dendritic sub-units whereas the former is only possible with spiking dendrites. Finally, we show how linearly non-separable functions can be computed by a generic two-compartment biophysical model and a realistic neuron model of the cerebellar stellate cell interneuron. Taken together our results demonstrate that passive dendrites are sufficient to enable neurons to compute linearly non-separable functions.


An audit of medicolegal conferencing.
In the English civil justice system, experts involved in a case are now commonly required to confer before the hearing and identify the areas of agreement and disagreement. A prospective study of 50 consecutive medicolegal conferences of experts was undertaken, with a view to defining their benefits, weaknesses and the optimum conference format. A record was kept of the dates of first instruction, court deadlines, and date, time and duration of conferences, together with related calls and correspondence. The manner of preparation of the statement was noted, the level of agreement/disagreement, any compromise, any later modifications of the draft, and the author's fees. Subsequently the instructing solicitors were asked to comment on the suitability of the joint statement and its contribution to settlement. Medicolegal conferencing is time-consuming and expensive. It may be of limited value where there is little or no difference of opinion, either between experts in a single field or between experts in different fields. The instructing solicitors must ensure that the participants receive, in advance of the conference, copies of all relevant documents including medical reports and medical records. An agenda is helpful in ensuring that matters of importance are not overlooked. Conferences are more effective when held in person than when conducted by telephone. The joint statement is best dictated in the presence of all participants during or after the conference. To ensure the most efficient and economical use of consultant time a formal combined audit of conferencing should be undertaken by the medical and legal professions.